1.1 Field of the Invention
The present invention provides compounds, compositions, and methods for treating Alzheimer's disease. The present invention has applications in the areas of medicine, medicinal chemistry, and neurobiology.
1.2 The Related Art
Alzheimer's Disease (“AD”), also known as Alzheimer disease, senile dementia of the Alzheimer type (“SDAT”), primary degenerative dementia of the Alzheimer's type (“PDDAT”), or simply as “Alzheimer's”, named after Alois Alzheimer, who first described the ailment in 1906, is the most common form of dementia, usually striking those over 65 years. “Early-onset Alzheimer's”, which affects far fewer individuals, can strike much earlier. (Hereinafter, all forms of the disease will be referred to as “Alzheimer's” or “AD” unless specifically noted otherwise.) Current estimates place the number of Alzheimer's sufferers at nearly 27 million; the disease is expected to affect about one in every 85 persons by 2050. Alzheimer's is incurable, degenerative, and terminal.
Although the etiology of the disease is not known, and the course of the disease varies among individuals, there are common early symptoms, such as the inability to acquire new memories as manifested by failing to recall recent observations. Often, these early symptoms are mistakenly identified as “age-related” concerns or stress reactions. The diagnosis of AD is typically made using behavioral assessments, cognitive tests, and brain scans. However, the disease develops over a variable period before becoming fully apparent and often goes undiagnosed for years.
Symptoms of advancing AD include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss, and the general withdrawal of the sufferer as their senses decline. The sufferer's bodily functions slowly deteriorate until they are lost, leading to death. Individual prognosis is difficult to assess, as the duration of the disease varies. The mean life expectancy following diagnosis is approximately seven years; fewer than three percent of individuals live more than fourteen years after diagnosis.
Current theories describing the mechanism of Alzheimer's posit that the disease is related to the development of various plaques and tangles in the brain. Analysis of these plaques reveals an abundance of the so-called Aβ peptide, an approximately 40-residue protein fragment partially overlapping a sequence in the transmembrane and cytosolic domains of a 100 kDa gene product termed the amyloid precursor protein (“APP”). The Aβ peptide has been shown to occur in both monomeric and oligomeric forms, with Aβ oligomers having been demonstrated to be toxic to neurites in cell culture. Formation of such oligomers is accentuated by APP mutations that are associated with familial AD. Thus, in theory a small molecule which blocked Aβ oligomer formation in cell culture would be a promising candidate for an AD therapeutic or prophylactic. But many questions remain to be answered before a comprehensive theory of the AD disease process is available.
Current treatments can offer only minor symptomatic relief; there are no treatments capable of slowing or halting disease progression. But the lack of effective palliative treatments or outright cure is not for any lack of trying: As of 2008, more than 500 clinical trials have been conducted on possible treatments for AD, but none has shown significant results. Both the professional and popular literature and media have touted various life-styles to prevent Alzheimer's disease, but there is scant evidence of any causal link between these recommendations and disease prevention or improvement.
Because AD cannot be cured and is degenerative, the careful management of patients suffering from this disease is essential—and usually falls heavily on family members in view of the astronomical costs of professional care. The pressures resulting for taking care of Alzheimer's patients impact nearly every aspect of the caregiver's life, including their social, psychological, physical, and economic well being. Not surprisingly, Alzheimer's Disease is one of the most costly diseases among all industrial societies.
New treatments are thus needed desperately to combat this horrific disease. The present invention meets this and other needs.